calpain and Polycystic-Ovary-Syndrome

Recent evidences suggest that common functional polymorphisms in the promoter region of the Calpain-10 gene may have an impact on an individual's susceptibility to polycystic ovary syndrome (PCOS), but individually published results are inconclusive. Our meta-analysis is aimed to provide a more precise estimation of the relationships between Calpain-10 genetic polymorphisms and PCOS risk. An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from inception through April 1st, 2013. This meta-analysis was performed using the STATA 12.0 software. The crude odds ratio (OR) with 95% confidence interval (CI) was calculated. Fourteen case-control studies were included with a total of 2123 PCOS patients and 3612 healthy controls. Nine common SNPs in the Calpain-10 gene were addressed. Our meta-analysis indicated that UCSNP-19, UCSNP-63 and UCSNP-45 polymorphisms in the Calpain-10 gene might be associated with increased PCOS risk. However, no statistically significant association was observed in UCSNP-43, UCSNP-22, UCSNP-43, UCSNP-45, UCSNP-56, UCSNP-58, and UCSNP-110 polymorphisms. Further subgroup analysis by ethnicity revealed that UCSNP-19, UCSNP-63 and UCSNP-45 polymorphisms might decrease the risk of PCOS among Asian populations, but not among Caucasian populations. The current meta-analysis indicates that UCSNP-19, UCSNP-63 and UCSNP-45 polymorphisms in the Calpain-10 gene may be risk factors for PCOS, especially among Asian populations.

Topics: Algorithms; Asian People; Calpain; Female; Genetic Predisposition to Disease; Humans; Polycystic Ovary Syndrome; Polymorphism, Genetic; Promoter Regions, Genetic; Publication Bias; Regression Analysis; Risk Factors

Polycystic ovary syndrome (PCOS) is a highly complex endocrine disorder, characterized by hyperandrogenemia, menstrual irregularities and polycystic ovaries. A strong genetic component to the etiology of PCOS is evident. However, due to the genetic and phenotypic heterogeneity of PCOS and the lack of insufficiently large cohorts, studies to identify specific contributing genes to date have yielded only few conclusive results. In this review we discuss the current status of the genetic analysis of PCOS including the results of numerous association studies with candidate genes involved in TGF-β and insulin signaling, type 2 diabetes mellitus and obesity susceptibility. Furthermore, we address current challenges in genetic studies of PCOS, and the promise of new approaches, including genome-wide association studies and next-generation sequencing.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Calpain; Diabetes Mellitus, Type 2; Female; Fibrillins; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Insulin; Insulin Receptor Substrate Proteins; Microfilament Proteins; Polycystic Ovary Syndrome; Polymorphism, Genetic; Proteins; Receptor, Insulin; Sex Hormone-Binding Globulin; Transcription Factor 7-Like 2 Protein

  To investigate the association between CAPN 10 gene polymorphism and polycystic ovary syndrome (PCOS) susceptibility.. Meta-analysis of published case-control studies of four single nucleotide polymorphisms (SNPs) in CAPN 10 and PCOS susceptibility..   Women with PCOS..   Odds ratios (ORs) and 95% confidence intervals (CIs) for heterozygous, homozygous, dominant model, recessive model and allele..   A total of 11 studies were involved in the meta-analysis. UCSNP-63 was significantly associated with PCOS, with homozygous carriers (TT vs CC: OR = 0·64; 95% CI: 0·45-0·90) and recessive model (TT vs CC and CT: OR = 0·64; 95% CI: 0·45-0·90) being protective factors. In addition, UCSNP-19 was significantly associated with PCOS, with recessive model (ins/ins vs del/del and del/ins: OR = 0·72, 95% CI: 0·59-0·88) and insert allele (ins vs del: OR = 0·85, 95% CI: 0·76-0·96) being protective factors, while heterozygous carriers (del/ins vs del/del: OR = 1·56, 95% CI: 1·24-1·94) and deletion allele (del vs ins: OR = 1·18, 95% CI: 1·04-1·32) being risk factors. However, no significant associations were found between UCSNP-44, -43 and PCOS. Moreover, the results of the Rotterdam criteria subgroup analysis were similar with that of overall analysis..   This is the first report on the association between CAPN 10 UCSNP-63 and PCOS in genotype, with homozygous carriers and recessive model being protective factors. Additionally, insert allele and recessive model of UCSNP-19 are protective factors, while deletion allele and heterozygous genotype are risk factors for PCOS development.

Topics: Alleles; Calpain; Case-Control Studies; Female; Gene Frequency; Genes, Dominant; Genes, Recessive; Genetic Predisposition to Disease; Genotype; Humans; Models, Genetic; Odds Ratio; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide

PCOS is known to be associated with an increased risk of T2DM and has been proposed to share a common genetic background with T2DM. Recent studies suggest that the Calpain-10 gene (CAPN10) is an interesting candidate gene for PCOS susceptibility. However, contradictory results were reported concerning the contribution of certain CAPN10 variants, especially of UCSNP-44, to genetic predisposition to T2DM, hirsutism, and PCOS. By means of MALDI-TOF MS technique, we genotyped an expanded single nucleotide polymorphism panel, including the CAPN10 UCSNP-44, -43, -56, ins/del-19, -110, -58, -63, and -22 in a sample of 146 German PCOS women and 606 population-based controls. Statistical analysis revealed an association between UCSNP-56 and susceptibility to PCOS with an odds ratio (OR) of 2.91 (95% CI=1.51-5.61) for women carrying an AA genotype compared with GG. As expected, the 22-genotype of the ins/del-19 variant, which is in high linkage disequilibrium (r2=0.98) with UCSNP-56, was also significantly associated (OR=2.98, 95% CI=1.55-5.73). None of the additionally tested variants alone showed any significant association with PCOS. A meta-analysis including our study (altogether 623 PCOS cases and 1,224 controls) also showed significant association only with ins/del-19. The most common haplotype TGG3AGCA was significantly associated with a lower risk for PCOS (OR=0.487, P=0.0057). In contrast, the TGA2AGCA haplotype was associated with an increased risk for PCOS (OR=3.557, P=0.0011). By investigating a broad panel of CAPN10 variants, our results pointed to an allele dose-dependent association of UCSNP-56 and ins/del-19 with PCOS.

Topics: Adult; Calpain; Case-Control Studies; Female; Gene Frequency; Genotype; Haplotypes; Humans; Linkage Disequilibrium; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; White People

Polycystic ovary syndrome (PCOS) is a very common endocrine disorder that has a strong genetic component and is characterized by polycystic ovaries, hyperandrogenemia, and menstrual irregularity. During the past decade, the roles of more than 70 candidate genes have been evaluated for a causal role in PCOS; however, because of genetic and phenotypic heterogeneity and underpowered studies, the results of many of these studies remain inconclusive. Here, the results of the genetic analysis of several candidate genes and gene regions-CYP11A (encoding cytochrome P450, family 11, subfamily A polypeptides), CAPN10 (encoding calpain 10), the insulin gene VNTR (variable number of tandem repeats), and D19S884 (a dinucleotide repeat marker mapping to chromosome 19p13.2)-are discussed in detail. Although past genetic studies of PCOS have yielded only modest results, resources and techniques have been assembled to remedy the major deficits of these early studies, promising that the next few years will be a very exciting and rewarding era for the genetic analysis of PCOS.

Topics: Calpain; Cholesterol Side-Chain Cleavage Enzyme; Chromosomes, Human, Pair 19; Dinucleotide Repeats; Female; Genetic Predisposition to Disease; Humans; Insulin; Minisatellite Repeats; Pedigree; Polycystic Ovary Syndrome

Topics: Calpain; Female; Gene Frequency; Humans; Polycystic Ovary Syndrome; Polymorphism, Genetic

Topics: Adult; Alleles; Biomarkers; Calpain; Case-Control Studies; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Insulin; Insulin Receptor Substrate Proteins; Middle Aged; Odds Ratio; Phenotype; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; PPAR gamma; Receptor, Insulin; Young Adult

To highlight a possible association of Calpain (CAPN 10) gene UCSNP-43 polymorphism with hormonal and metabolic traits of young women with different phenotypes of polycystic ovary syndrome (PCOS).. PCOS women were genotyped for the CAPN 10 gene UCSNP-43 polymorphism. A comparison of clinical and biochemical features of women with PCOS stratified on the basis of the CAPN 10 gene UCSNP-43 variants was assessed.. Anthropometric, hormonal and biochemical measurements were carried out in 668 PCOS women and 200 healthy controls. Subjects were also genotyped for the CAPN 10 gene UCSNP-43 polymorphism. The genotype frequency distributions between groups and controls were compared using the chi-square test. The association of the polymorphism with the clinical and biochemical features of the study cohort was estimated as well.. No association of the frequency of CAPN 10 gene UCSNP-43 polymorphism with PCOS was detected. No association of the polymorphism with the anthropometric, biochemical and hormonal features was detected both in PCOS and control women. The polymorphism was associated with serum Δ4 androstenedione (p = 0.018), as well as with 17-OH progesterone (17-hydroxyprogesterone) among women with PCOS phenotype A (p = 0.012).. CAPN 10 gene polymorphism UCSNP-43 is deprived of a metabolic contribution to cardiovascular disease (CVD). However, due to its association with androgen excess in phenotype A, CAPN 10 gene polymorphism UCSNP-43 could be used as a genetic marker for CVD in young PCOS women.

Topics: Adolescent; Adult; Alleles; Androgens; Calpain; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Phenotype; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Severity of Illness Index; Young Adult

Recent studies have suggested that calpain-10 (CAPN10) gene polymorphisms play a role in the susceptibility to polycystic ovary syndrome (PCOS). The aim of the present study was to evaluate the possible association between three single nucleotide polymorphisms (SNPs) in CAPN10 gene: UCSNP-43 (rs3792267), UCSNP-19 (rs3842570), and UCSNP-63 (rs5030952) and PCOS in Tunisian cases and control women. Study subjects included 127 women with PCOS (mean age 29.8 ± 4.7 year) and 150 healthy women (mean age 33.5 ± 5.6 year). CAPN10 genotyping was carried-out by direct PCR and PCR-RFLP. Linkage disequilibrium pattern in the genomic region explored was determined by HAPLOVIEW 4.2 while reconstruction of haplotypes was done using PHASE 2.1. The phylogenetic distribution of haplotypes in the population was determined by ARLEQUIN 2.000. Six haplotypes were observed. None of SNPs associated with PCOS or its components while the haplotype H4 associated with the phenotype PCOS-obese (P < 0.025). Moreover the pair of haplotypes H1/H4 strongly associated with high blood-pressure (OR = 14.4, P < 0.012). This work confirms the association of CAPN10 gene with metabolic components in PCOS and highlights the role of haplotypes as strong and efficient genetic markers.

Topics: Adult; Alleles; Calpain; Case-Control Studies; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Haplotypes; Humans; Linkage Disequilibrium; Phylogeny; Polycystic Ovary Syndrome; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Risk; Tunisia

Polycystic Ovary Syndrome (PCOS) is known to be characterized by metabolic disorder in which hyperinsulinemia and peripheral insulin resistance are central features. Given the physiological overlap between PCOS and type-2 diabetes (T2DM), and calpain 10 gene (CAPN10) being a strong candidate for T2DM, a number of studies have analyzed CAPN10 SNPs among PCOS women yielding contradictory results. Our study is first of its kind to investigate the association pattern of CAPN10 polymorphisms (UCSNP-44, 43, 56, 19 and 63) with PCOS among Indian women. 250 PCOS cases and 299 controls from Southern India were recruited for this study. Allele and genotype frequencies of the SNPs were determined and compared between the cases and controls. Results show significant association of UCSNP-44 genotype CC with PCOS (p = 0.007) with highly significant odds ratio when compared to TC (OR = 2.51, p = 0.003, 95% CI = 1.37-4.61) as well as TT (OR = 1.94, p = 0.016, 95% CI = 1.13-3.34). While the haplotype carrying the SNP-44 and SNP-19 variants (21121) exhibited a 2 fold increase in the risk for PCOS (OR = 2.37, p = 0.03), the haplotype containing SNP-56 and SNP-19 variants (11221) seems to have a protective role against PCOS (OR = 0.20, p = 0.004). Our results support the earlier evidence for a possible role of UCSNP-44 of the CAPN10 gene in the manifestation of PCOS.

Topics: Adolescent; Adult; Alleles; Calpain; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; India; Middle Aged; Models, Statistical; Phenotype; Polycystic Ovary Syndrome; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Temperature

We investigated whether the CAPN-10 polymorphism UCSNP-43, -19, and -63 contribute, either individually or as haplotype/diplotype, to the susceptibility of polycystic ovary syndrome (PCOS) or related quantitative traits in Korean women. Our data showed that 111 haplotype and 111/121 and 111/111 diplotypes in the CAPN-10 gene were associated with a significantly increased risk of PCOS, and 112 haplotype and 121/121 and 112/122 diplotypes were associated with decreased risk of PCOS in the Korean population.

Topics: Adult; Calpain; Female; Genetic Predisposition to Disease; Humans; Incidence; Korea; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors

This study was designed in order to examine the relationship between Calpain 10 [single-nucleotide polymorphism (SNP) 19,43,44,63] gene polymorphisms and clinical and hormonal characteristics in women with polycystic ovary syndrome (PCOS).. One hundred and seven patients with PCOS and 114 healthy subjects were included in this study. Serum levels of sex steroids were measured for each individual. Insulin resistance (IR) was evaluated by the homeostasis model assessment (HOMA) and quantitative insulin-sensitivity check index (QUICKI) methods. Insulin and glucose responses to the oral glucose tolerance test (OGTT) were analyzed by calculating the areas under the curve for insulin (AUCI) and glucose by the trapezoidal methods.We used PCR and restriction fragment length polymorphism technique to examine Calpain 10 SNP 19, 43, 44, and 63 polymorphisms.. Allele distribution of Calpain 10 SNP 44 gene polymorphism was observed as significantly different between the groups. Calpain 10 SNP 44 TC genotype was found to be increased in PCOS subjects (69.15%) compared to the control subjects (50%). However, when compared to control subjects, patients with PCOS had similar Calpain 10 SNP 19, Calpain 10 SNP 43, and SNP 63 gene polymorphisms. When compared with normal Calpain 10 gene SNP 44 allele in PCOS subjects, subjects with PCOS having Calpain 10 gene SNP 44 allele polymorphism had higher free testosterone, androstenedione, DHEA-S, and fasting insulin levels. Also, PCOS women with Calpain 10 gene SNP 44 allele polymorphism had high Ferriman-Gallwey (F-G) score, acne, prevalence of menstrual disturbances, waist-hip ratio, HOMA-IR, AUCI levels and low QUICKI levels.. The findings show that Calpain 10 gene SNP 44 allele polymorphism may have a role in PCOS pathogenesis. However, larger-scale studies are needed in this field.

Topics: Adult; Androstenedione; Blood Glucose; Calpain; Dehydroepiandrosterone Sulfate; Female; Humans; Insulin Resistance; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Testosterone

Polycystic ovary syndrome (PCOS), whose genetic basis is not completely well understood, is the most common endocrine disorder in women and it typically develops during adolescence. The aim of this study is to investigate the possible association between single nucleotide polymorphisms (SNPs) of FSHR, CYP17, CYP1A1, CAPN10, INSR, SERPINE1 genes and PCOS in adolescent girls.. DNA samples from forty-four adolescent girls with PCOS and 50 healthy controls were analyzed by PCR-RFLP and direct DNA sequencing to determine the genotypic frequency of 17 different polymorphic loci on the FSHR (A307T, N680S), CYP17 (-34 T/C), CYP1A1 (T6235C), CAPN10 (44, 43, 19, 63), INSR (exon 17 C/T), SERPINE1 (4G/5G) genes. Genotyping of exon 12 (six polymorphisms) and intron 12 (one polymorphism) of INSR gene by direct DNA sequencing was performed for the first time in this study.. No significant differences were observed in the genotype and allele distributions of above mentioned polymorphisms between cases and control groups.. Our data does not support an association between SNPs of FSHR, CYP17, CYP1A1, CAPN10, INSR, SERPINE1 genes and susceptibility to PCOS or related traits in Turkish adolescent girls.

Topics: Adolescent; Antigens, CD; Calpain; Cytochrome P-450 CYP1A1; Female; Genetic Predisposition to Disease; Humans; Plasminogen Activator Inhibitor 1; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Receptor, Insulin; Receptors, FSH; Steroid 17-alpha-Hydroxylase

To investigate the relationship between single nucleotide polymorphism-56 (SNP-56) in calpain-10 (CAPN-10) gene and polycystic ovary syndrome (PCOS) in Chinese.. The genotypes of SNP-56 of CAPN-10 were determined through polymerase chain reaction Tm-shift genotyping method in 638 local women in Shandong Province. Among them, 334 were patients with PCOS (PCOS group) and 304 were normal women (control group). The baseline parameters including levels of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol (E2), testosterone (T) and lipid,as well as the body mass index (BMI) and waist/hip ratio (WHR) were measured. Glucose tolerance and insulin releasing before and after loading with 75 g of glucose were also assayed.. (1) The frequencies of two allelotypes or three genotypes did not differ between PCOS women and normal women (P > 0.05). (2) In PCOS group, patients with AA genotype had a significantly higher plasma glucose of 180 minutes OGTT (5.7 +/- 2. 2)mmol/L [P < 0.01 compared to GA genotype (4.9 +/- 1.2) mmol/L, P < 0.01 compared to GG genotype (4.9 +/- 1.4) mmol/L] and serum total cholesterol (TC) level (4.9 +/- 1.0) mmol/L [P < 0.05 compared to GA genotype (4.5 +/- 0.9) mmol/L]. (3) Compared to PCOS patients with GA + GG genotype (P < 0.05, P < 0.01) or GG genotype (P < 0.05, P < 0.01), there was significantly higher attack rate of diabetes and tumor in the family history of patients with AA genotype.. These findings suggest that CAPN-10 gene SNP-56 which may not contribute to the genetic susceptibility of PCOS plays a role in glucose and lipid metabolism in Chinese PCOS patients. It may also be correlated with attack rate of diabetes and tumor in the family history of PCOS patients.

Topics: Adolescent; Adult; Blood Glucose; Calpain; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Lipids; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Triglycerides; Young Adult

Cardiovascular disease is the leading cause of morbidity and mortality in the industrialized world. Familial aggregation of cardiovascular risk factors is a frequent finding, but genetic factors affecting its presentation are still poorly understood. The calpain 10 gene (CAPN10) has been associated with type 2 diabetes (T2DM), a complex metabolic disorder with increased risk of cardiovascular disease. Moreover, the CAPN10 gene has been associated with the presence of metabolic syndrome (MS) in T2DM and in polycystic ovary syndrome (PCOS). In this work, we have analysed whether the polymorphisms UCSNP44, -43, -19 and -63 are related to several cardiovascular risk factors in the context of MS. Molecular analysis of CAPN10 gene was performed in 899 individuals randomly chosen from a cross-sectional population-based epidemiological survey. We have found that CAPN10 gene in our population is mainly associated with two indicators of the presence of insulin resistance: glucose levels two hours after a 75-g oral glucose tolerance test (OGTT) and HOMA values, although cholesterol levels and blood pressure values are also influenced by CAPN10 variants. In addition, the 1221/1121 haplogenotype is under-represented in individuals that fulfil the International Diabetes Federation (IDF) diagnostic criteria for MS. Our results suggest that CAPN10 gene is associated with insulin resistance phenotypes in the Spanish population.

Topics: Adult; Aged; Blood Glucose; Calpain; DNA; Female; Humans; Insulin Resistance; Lipids; Male; Metabolic Syndrome; Middle Aged; Phenotype; Polycystic Ovary Syndrome; Spain; White People

Studies have suggested that the Calpain-10 gene polymorphisms may play a role in polycystic ovary syndrome (PCOS) susceptibility. Thus, the aim of the present study was to evaluate the possible association between three single nucleotide polymorphisms (SNPs) in the calpain-10 gene (UCSNPs -43, -19, and -63) and polycystic ovary syndrome (PCOS) in Chilean women.. Fifty women with PCOS (28.8+/-8.2 y) and 70 healthy women (28.6+/-8.6 y) were included in this study. Serum lipids, hormonal status, fasting glucose, oral glucose tolerance test (OGTT), insulin, HOMAIR, and uric acid levels were determined by conventional methods. The calpain-10 gene variants were detected by PCR and PCR-RFLP, respectively.. The presence of uncommon allele (A) for the UCSNP-43 was associated with increased risk of PCOS (odds ratio=1.93, 95% CI: 1.11-3.34). The UCSNP-63 (OR=1.11, 95% CI: 0.59-2.11) and UCSNP-19 (OR=0.93, 95% CI: 0.55-1.57) were not associated to PCOS. However, the PCOS women carrying the CC genotype for UCSNP-63 exhibited higher values of total cholesterol and LDL-C (P<0.05). Similarly, control women carrying the CC genotype showed higher serum levels of triglycerides, HDL-C and uric acid (P<0.05).. Our data suggest the contribution of CAPN10 UCSNP-43 gene polymorphism to PCOS in Chilean women. However, further studies with larger samples are necessary to confirm this observation.

Topics: Adolescent; Adult; Alleles; Blood Glucose; Calpain; Chile; Cholesterol; Cholesterol, LDL; DNA; Female; Gene Frequency; Glucose Tolerance Test; Hormones; Humans; Insulin; Lipids; Polycystic Ovary Syndrome; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Reverse Transcriptase Polymerase Chain Reaction; Risk; Uric Acid; Young Adult

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with individual susceptibility determined by genetic and environmental risk factors. Recently, studies have evaluated the CAPN10 gene in PCOS patients, suggesting that different alleles may play a role in PCOS susceptibility. We performed a cross-sectional study with 88 southern Brazilian hirsute patients with PCOS or idiopathic hirsutism (IH) to assess the influence of CAPN10 genetic variants on clinical and biochemical features of metabolic syndrome. PCOS patients were defined by oligo/amenorrheic cycles (<9 cycles/year), increased levels of serum testosterone and/or free androgen index, and exclusion of other disorders associated with hyperandrogenism. IH was diagnosed in hirsute patients with regular ovulatory cycles (luteal-phase progesterone levels >3.8 ng/ml), normal androgen levels, and without any known underlying disease (n = 29). Metabolic syndrome was defined according to the 2001 criteria of the National Cholesterol Education Program, Adult Treatment Panel III. UCSNP-43 polymorphism of CAPN10 was related to metabolic syndrome (p = 0.047) in PCOS; UCSNP-19 and UCSNP-63 were not associated with phenotypic traits in PCOS. These results provide evidence that CAPN10 gene UCSNP-43 polymorphisms may influence the PCOS metabolic phenotype. This should be further confirmed in large population-based studies.

Topics: Adult; Blood Glucose; Body Mass Index; Brazil; Calpain; Female; Hirsutism; Humans; Metabolic Syndrome; Phenotype; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The aim of the present study was to investigate the role of CALPAIN-5 (CAPN5) gene in PCOS susceptibility.. We analysed four intronic polymorphisms of the CAPN5 gene in 148 well-characterized women with PCOS and 606 unrelated controls. We performed a case-control study and an intracohort analysis of clinical characteristics associated with PCOS.. Analysis of haplotypes distribution between PCOS population compared to controls showed a strong deviation (P = 0.00029). The haplotypes GGCA and GGTG were overrepresented in PCOS patients (P = 0.009 and P = 0.001, respectively). In addition, we identified several CAPN5 haplotypes associated with phenotypic differences observed between PCOS patients, such as the presence of obesity (P = 0.02), cardiovascular complications (P = 0.02), familial antecedents of obesity (P = 0.003) and of hypertension (P = 0.007) and type 2 diabetes mellitus aggregation (P = 0.04).. These results suggest a role of CAPN5 gene in PCOS susceptibility in humans. Moreover, novel candidate risk alleles have been identified, within CAPN5 gene, which could be associated with important phenotypic and prognosis differences observed in PCOS patients.

Topics: Alleles; Calpain; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Obesity; Phenotype; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Risk Factors

Recently, several research groups have evaluated CAPN10 gene in polycystic ovarian syndrome (PCOS) patients and other phenotypes, including hirsutism or intermediate phenotypes of PCOS. Molecular genetic analysis of CAPN10 gene indicates that different alleles may play a role in PCOS susceptibility and could be associated with idiopathic hirsutism. However, these observations are not exempt from controversy, because independent studies cannot replicate these preliminary findings. We present a haplotype-phenotype correlation study of CAPN10 haplotypes in 148 women showing ecographically detected polycystic ovaries (PCO) combined with one or more of these clinical symptoms: amenorrhea or severe oligomenorrhea, hyperandrogenism, and anovulatory infertility, as well as 93 unrelated controls. We have reconstructed and analyzed 482 CAPN10 haplotypes in patients and controls. We detected the association of UCSNP-44 allele with PCO phenotype in the Spanish population (P = 0.02). In addition, we identified several CAPN10 alleles associated to phenotypic differences observed between PCO patients, such as the presence of hypercholesterolemia (haplotype 1121, P = 0.005), presence of hyperandrogenic features (P = 0.05), and familial cancer incidence (haplotype 1111, P = 0.0005). Our results confirm the association of UCSNP-44 allele with PCO phenotype in the Spanish population. Moreover, we have identified novel candidate risk alleles and genotypes, within CAPN10 gene, that could be associated with important phenotypic and prognosis differences observed in PCOS patients.

Topics: Amenorrhea; Calpain; Cholesterol; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Hyperandrogenism; Phenotype; Polycystic Ovary Syndrome; Risk Factors

Polycystic ovary syndrome (PCOS) is characterized by chronic anovulation infertility, hyperandrogenemia, and frequently insulin resistance. This study investigated whether polymorphisms in the CAPN10 gene are related with PCOS etiology. The allelic frequencies and genotypes of CAPN10 polymorphisms UCSNP-44, 43, 19, and 63 were determined in 55 well characterized women with polycystic ovaries and 93 unrelated healthy controls using spectrofluorimetric analyses and real-time PCR. Our data indicate that CAPN10 UCSNP-44 allele is associated with PCOS in the Spanish population (P = 0.01). These results support a role of Calpain 10 gene in PCOS susceptibility in humans.

Topics: Calpain; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is associated with an increased risk of impaired glucose tolerance and type 2 diabetes. Recent evidence suggests that variation in the gene encoding the cysteine protease calpain-10 influences susceptibility to type 2 diabetes. The present study was undertaken to determine whether variation in this gene is associated with quantitative traits pertinent to the pathogenesis of PCOS and diabetes. We studied 212 women with PCOS (124 white of European ancestry, 57 African-American, 13 Hispanic, 13 Asian-American, and 5 Middle-Eastern). Each subject was genotyped for 3 DNA polymorphisms in the calpain-10 gene associated with type 2 diabetes (SNP-43, -19, and -63). The white and African-American subjects were examined for association of these polymorphisms with phenotypic features of PCOS and type 2 diabetes. There were not enough individuals in the other groups for similar genotype/phenotype analyses. Nineteen (9%) of the 212 women with PCOS were diabetic and were not included in the genotype/phenotype analyses. Twelve (63%) of these subjects were African-American. Phenotypic traits in nondiabetic white probands did not differ whether analyzed for each individual SNP (SNP-43, -19, -63) or haplotype combination. Nor was there association of SNP-43, -19, or -63 with any of the phenotypic features of type 2 diabetes or PCOS in nondiabetic African-Americans. However, nondiabetic African-Americans with the 112/121-haplotype combination had significantly higher insulin levels, in response to an oral glucose challenge, as reflected in the area under the insulin curve (257,021 +/- 95,384 vs. 136,240 +/- 11,468 pmol/min; P = 0.03), compared with those with other haplotypes. This finding was particularly notable because the 112/121 subjects were less obese. The difference between groups in area under the insulin response curve remained significant (P = 0.002 by analysis of covariance) after adjustment for body mass index. In addition to its association with insulin levels in African-Americans, the 112/121-haplotype combination was associated with an approximate 2-fold increase in risk of PCOS in both African-Americans and whites.

Topics: Administration, Oral; Adult; Black or African American; Black People; Calpain; Diabetes Mellitus, Type 2; DNA; Female; Genetic Predisposition to Disease; Genotype; Glucose; Haplotypes; Humans; Insulin; Phenotype; Polycystic Ovary Syndrome; Polymorphism, Genetic; Quantitative Trait, Heritable

Variation within the calpain-10 gene (CAPN10) has been proposed to account for linkage to type 2 diabetes on chromosome 2q in Mexican-Americans, and associations with diabetes have been reported in several other populations. Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility. Using both family based and case-control association resources (146 parent-offspring trios; 185 additional PCOS cases; 525 control subjects, all of European ancestry), we sought association between CAPN10 variation and PCOS, focusing on four single nucleotide polymorphism (SNP) variants (SNP-44, SNP-43; SNP-19; SNP-63). On single-locus transmission disequilibrium analysis in the 146 trios, there was nominal evidence (P = 0.03) of excess transmission of the more common allele at SNP-63. This association was not, however, replicated in the case-control analysis. No other significant associations were observed at the single-locus or haplotype level in either the transmission-disequilibrium or case-control analyses. The relative risk for the high-risk diabetes susceptibility 112/121 genotype (SNPs 43-19-63) was 0.84 (95% confidence intervals, 0.40-1.71). No associations were seen with intermediate traits of relevance to diabetes and PCOS pathogenesis. We have found no evidence from these analyses that CAPN10 gene variation influences susceptibility to PCOS.

Topics: Adult; Calpain; Case-Control Studies; Chromosome Mapping; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Polycystic Ovary Syndrome; Quantitative Trait, Heritable